RT Journal Article
SR Electronic
T1 Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5689
OP 5700
DO 10.1158/1078-0432.CCR-20-1065
VO 26
IS 21
A1 Wildes, Tyler J.
A1 Dyson, Kyle A.
A1 Francis, Connor
A1 Wummer, Brandon
A1 Yang, Changlin
A1 Yegorov, Oleg
A1 Shin, David
A1 Grippin, Adam
A1 Dean, Bayli DiVita
A1 Abraham, Rebecca
A1 Pham, Christina
A1 Moore, Ginger
A1 Kuizon, Carmelle
A1 Mitchell, Duane A.
A1 Flores, Catherine T.
YR 2020
UL http://clincancerres.aacrjournals.org/content/26/21/5689.abstract
AB Purpose: Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape.Experimental Design: We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT.Results: Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells.Conclusions: These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.